The data from this preliminary study in
HIV-infected NNRTI resistant patients suggests that capravirine may be useful
for some patients with NNRTI resistance. In vitro (test tube) testing of viruses
from humans with NNRTI resistance in this study shows 50% (26/52) of viruses
with resistance to NNRTIs (efavirenz, nevirapine and delavirdine) were fully
sensitive to capravirine. When the key NNRTI mutation K103N was present as a
single mutation or as part of a multiply mutant virus 18 of 28 (64%) viruses
were fully sensitive (4/28 had intermediate sensitivity to capravirine) to CPV
while most of these viruses were resistant to nevirapine & efavirenz. The
more NNRTI mutations a patient had the less sensitive the patient was to capravirine.
When NNRTI resistance was present in these viruses without the K103N being present
only 3 of 19 viruses were fully sensitive to capravirine and 3 had intermediate
sensitivity to capravirine. This data is preliminary and more human studies
must be conducted to evaluate the actual benefit and how to use this drug for
patients with NNRTI resistance.

Capravirine is a non-nucleoside reverse
transciptase inhibitor (NNRTI) being developed by Agouron/Pfizer for patients
with NNRTI resistance. The drug was being evaluated in HIV-infected NNRTI resistant
individuals when animal toxicity was discovered. Vasculitis is a condition causing
inflammation of the blood vessels and was found during studies in dogs. As a
result, the FDA placed development & this study on hold. Twenty patients
in this study who had good viral load reductions on the Capravirine containing
regimen (I think they were also receiving PI therapy) they were receiving were
permitted to continue taking the drug and follow-up data has yet to be released.
Agouron is in discussions with the FDA and hopes to resume development of Capravirine.

At this year's Resistance Workshop (June,
2001), Agouron reported Capravirine resistance data from a study of 71 NNRTI
experienced individuals. It's been previously reported that resistance to Capravirine
(CPV) in vitro emerged more slowly and less frequently, and more often multiple
mutations were seen leading to resistance than with other NNRTIs (14th Intl
Conference on Antiviral research, Seattle, WA 2001). In Seattle, it was reported
that EC50 values (amount of drug) of 114nM or less showed potent antiviral activity
against NNRTI resistant viruses from plasma of ART experienced patients. In
this study, the authors reported CPV showed potent in vitro antiviral activity
with EC50 values <70 nM for 45 of 52 (86%) of patient viral isolates tested.
They also reported that of 28 viruses tested from the blood of NNRTI resistant
patients, 20 (71%) showed no resistance (n=13) or intermediate resistance (n=7;
<10-fold resistance).

BRIEF SUMMARYIn this study of patients with NNRTI experience & resistance, 8 of 9
patients with the single NNRTI mutation K103N were still sensitive to capravirine.
Of 12 patients with 2 NNRTI mutations including the K103N, 7 had full sensitivity
to CPV and 2 viruses had intermediate resistance to CPV. 3 of 5 viruses with
3 NNRTI mutations including the K103N were sensitive to CPV. Of 19 viruses without
the K103N mutation 17 had full resistance to EFV & DLV, 11 were still sensitive
to DLV, but only 3 were sensitive to CPV. Three of these 19 viruses had intermediate
CPV resistance and 13 had full CPV resistance.

THIS STUDY
This is a study of adults failing a NNRTI containing regimen who were PI naïve
(except patients who switched from a PI to an NNRTI while blood HIV RNA was
<400 copies/ml). Of the 71 study participants, 62% were failing regimens
containing nevirapine (NVP), 32% efavirenz (EFV), 1% emivirine, 5% none reported.
Blood samples were collected at baseline and evaluated for phenotypic resistance
in 53 patients and/or for genotypic resistance in 55 patients. They had both
pheno- and geno- test results available for 51 isolates. The investigators used
the Antivirogram (Virco) phenotypic resistance test. Drug specific cut-off values
determined by Virco for designating resistance were >8, >6 and >10
fold for NVP, delavirdine (DLV), and EFV, respectively. Because specific cut-off
values for CPV have not yet been determined, CPV sensitivity was designated
as sensitive, intermediate, or resistant with <4-fold, 4-10 fold, or >10
fold reductions in sensitivity, respectively. Genotypic resistance was determined
also with the Virco Vircogen test.

RESULTS
The authors reported no significant reduction in susceptibility (<4-fold)
was seen in 26 of 52 (50%) of patient viral isolates tested. These isolates
were tested for sensitivity to NVP, EFV and DLV. And 13% (7/53) were sensitive
to NVP, 17% (9/53) to EFV, and 38% (20/53) to DLV. This was established using
the cutoffs defined by Virco of <8, <6, and <10 fold for each drug,
respectively. Genotypic test results showed the key NNRTI mutartion K103N was
the predominant mutation occurring and was seen alone or with up to 4 additional
NNRTI mutations in 29 of 55 (53%) of isolates examined. Full sensitivity to
CPV was reported to be seen in 18 of 28% (64%) of K103N containing isolates
tested. But, only 5 of the 28 K103N isolates remained sensitive to NVP, EFV,
or DLV. Two viruses (7%) of the 28 viruses with the K103N remained sensitive
to NVP, 4 (14%) to DLV, and 3 (11%).

CPV Potency Against Virus Containing
Single NNRTI K103N Mutation

In an analysis of 28 of 29 isolates available
that contain the K103N and for which they had genotypic and phenotypic resistance
test results, 9 patients had the K103N alone (1 patient had the K103N/K). Of
these 9 patients with the K103N as their only NNRTI mutation, 8 had 3.9 or less
CPV resistance and 1 patient had 9.5 fold CPV resistance. All the 9 patients
had high level resistance to NVP, DLV, and EFV (72 fold or greater).

CPV Potency vs Virus Double NNRTI Mutations
(including K103N)

12 of these 28 isolates had two NNRTI mutations
also containing the K103N mutation. The additional mutation included A98G, A98S,
V108I, Y181C, Y188L.H, P225H, P225H/P, G190G/A, and K238T. All of these patients
had high level resistance to EFV, NVP and DLV (1 patient had only 8.2 DLV resistance).
9 of the 12 patients had no or intermediate CPV resistance. 7 of the 12 patients
were sensitive to CPV. They had 3.1 fold CPV resistance or less (range 0.4-3.1).
3 of the 12 patients with double NNRTI mutations including the K103N had high
level CPV resistance (range 13.3-61.4).

CPV Potency Against Viruses with 3 or
More Mutations (including the K103N)

There were 5 viruses with 3 NNRTI mutations
each also containing the K103N, and 3 of these 5 viruses were sensitive to CPV
(range 0.7-2 fold CPV resistance). The 4th virus had 16 fold CPV resistance.
3 of the 4 viruses had high level resistance to EFV, DLV, and NVP. One virus
had 3 genotypic NNRTI mutations including the K103N, but little or no resistance
to all the NNRTIs including CPV (5.6 fold resistance to NVP, 2.3 fold to DLV,
1.1 fold to EFV and 0.7 fold to CPV). The fifth virus had 3 mutations including
the K103N and had high level resistance to CPV as well as the other NNRTIs.

Two viruses had 4 or 5 NNRTI mutations including
the K103N. One virus had high level resistance to NVP, EFV and DLV and intermediate
resistance (7.9 fold) to CPV. The 2nd virus was 17.1 fold resistant to CPV,
and had high level resistance to EFV and NVP (but no resistance to DLV).

Viruses Without the K103N Mutation

There were 25 patient virus isolates without
the K103N mutation and CPV was not sensitive to most of these viruses. 21 of
the 25 had single, double, triple or 4 NNRTI mutations without the K103N. These
other mutations included Y181C, Y188L, G190A/Q/S, A98S, V108I, M230L, K238T/K.
4 of the viruses had no NNRTI or NRTI mutations suggesting they may not have
been treatment experienced, and these patient viruses had no NNRTI resistance.
Investigators could not determine the genotypic resistance to 2 of the 25 viruses.
One of these 2 viruses had high level NVP & EFV resistance but no DLV resistance
and was 8.6 fold (intermediate) resistant to CPV. The second virus was sensitive
to CPV (2.2 fold) and had high level NVP resistant but was sensitive to DLV
& EFV.

Of the 20 viruses for which they had genotypic
& phenotypic test results, 3 were sensitive to CPV, 13 had high level CPV
resistance, 3 had intermediate CPV resistance (6.4-8.6 fold), and they were
unable to determine the phenotypic resistance to 1 virus. Interestingly, 11
of these viruses without the K103N mutation were high level resistant to EFV
and NVP but 9 were sensitive to DLV. This suggests that if you fail EFV or NVP
without the K103N mutation you may still be able to use DLV. But you might still
be on the way to DLV resistance, which could occur with a little more viral
evolution.